Diagnosis and Treatment of Alcoholic Liver Disease and Its Complications

Alcoholic liver disease (ALD) is a serious and potentially fatal consequence of alcohol use. The diagnosis of ALD is based on drinking history, physical signs and symptoms, and laboratory tests. Treatment strategies for ALD include lifestyle changes to reduce alcohol consumption, cigarette smoking, and obesity; nutrition therapy; and pharmacological therapy. The diagnosis and management of the complications of ALD are important for alleviating the symptoms of the disease, improving quality of life, and decreasing mortality.

alcoholic hepatitis with tender hep atomegaly, jaundice, fever, accumulation of fluid in the abdominal cavity (i.e., ascites), nervous system effects such as confusion and personality change (i.e., hepatic encephalopathy), anorexia, and fatigue. Other signs may include high white blood cell counts resembling those seen in leukemia (i.e., leukemoid reactions) and the rapid deterioration of kidney function (i.e., hepatorenal syndrome). Even in the absence of cir rhosis, the main vein that brings blood from the intestine and stomach into the liver (i.e., the portal vein) may come under increased pressure because of scarring of the liver, resulting in portal vein hypertension.
Ten to 20 percent of patients with alcoholic hepatitis develop cirrhosis, and up to 70 percent of alcoholic hepatitis patients go on to develop cirrhosis each year (Bird and Williams 1988). Women are at higher risk for developing cirrho sis, as are people who continue drinking or have severe alcoholic hepatitis (Pares et al. 1986). Some patients with alcoholic hepatitis who abstain still may develop cirrhosis, but others will have complete clinical and histologic recovery.
Patients with early stage alcoholic cir rhosis with no complications (i.e., wellcompensated) may be asymptomatic and have normal physical exams and normal routine blood tests of liver function and injury. In other patients, alcoholic fatty liver or alcoholic hepatitis often coexist and may be accompanied by hepatomegaly, an enlarged spleen (i.e., splenomegaly), or both. In cirrhotics with severe alco holic hepatitis, hepatomegaly or spleno megaly may be the dominant feature; in other patients, the signs and symp toms of portal vein hypertension (e.g., ascites and engorged veins [varices] in the esophagus) may predominate. As the disease advances, the liver decreases in size, the left hepatic lobe becomes more prominent, and the entire liver has a hard and nodular consistency. Spleno megaly of varying degrees is frequent.
In later stage cirrhosis with compli cations (i.e., decompensated disease), patients may have muscle wasting, ascites, and the adaptation of smaller vessels to handle increased blood flow (i.e., venous collateral circulation).
Other common signs are small starshaped vessels (i.e., spider angiomata) on the skin of the upper torso, blotchy redness on the palms (i.e., palmar ery thema), and contracture of the palm tissue, causing the ring and pinky finger to bend into the palm (i.e., Dupuytren's palmar contracture). Enlargement of the parotid gland (one of the salivary glands) and the lacrimal (tear) glands often is seen. Enlargement of the fin gertips may be found in patients who develop a problem with the way blood passes through the lungs, resulting in blood not being properly oxygenated. Other physical signs, which may be found during examination with a flexi ble fiberoptic instrument (i.e., endo scopy), include changes in the stomach lining that occur with portal hyperten sion, as well as engorged veins in the esophagus, stomach, or another part of the gastrointestinal tract, which expand as a consequence of increased pressure in the blood flow of the venous system. Patients with hepatic encephalopathy may have slow reaction times and mus cle tremors causing involuntary jerking of the hands.
ALD cannot be diagnosed based on any of the physical signs and symptoms alone. Laboratory tests often assist in the diagnosis of ALD. Almost all patients will have elevated liver enzymes. The level of the enzyme aspartate amino transferase (AST) will exceed that of alanine aminotransferase (ALT), but both will be below 300 international units per milliliter (IU/ml). When the ratio of AST to ALT is greater than 2, the most likely diagnosis is ALD. In some studies, more than 80 percent of patients attain this ratio.
Elevated blood levels of the liver enzyme gamma glutamyltransferase (GGT) indicate heavy alcohol use and liver injury. This test has greater ability to correctly test positive (i.e., sensitiv ity) but less ability to correctly test negative (i.e., specificity) than AST or ALT tests. Of the three enzymes, GGT is the best indicator of excessive alcohol consumption, but because GGT is present in many organs and because some drugs raise GGT levels, high GGT levels are not necessarily an indi cator of alcohol abuse.
Chronic alcohol consumption also may be associated with abnormally high triglyceride levels (i.e., hypertriglyceri demia), high blood levels of uric acid (i.e., hyperuricemia), and low amounts of potassium (i.e., hypokalemia) and magnesium, as well as an elevated index of red blood cell size (i.e., mean corpus cular erythrocyte volume [MCV]). Hyperuricemia and hypertriglyc eridemia often normalize with absti nence, and hypokalemia normalizes with adequate potassium replacement. Elevated MCV often is found in peo ple who ingest more than 50 grams of alcohol per day, 1 with sensitivity of 27 to 52 percent and specificity of 85 to 1 In the United States, a drink is considered to be 0.5 ounces (oz) or 15 grams of alcohol, which is equivalent to 12 oz (355 milliliters [ml]) of beer, 5 oz (148 ml) of wine, or 1.5 oz (44 ml) of 80-proof distilled spirits (USDHHS 2000).

Alcoholic Hepatitis
Cirrhosis 90 percent. The blood protein known as carbohydrate-deficient transferrin frequently is used to detect current or recent alcohol abuse, especially con sumption in excess of 60 grams per day (Nilssen et al. 1992;Litten et al. 1995), but there are no ideal tests to identify continuing alcohol intake.
An increased number of white blood cells (i.e., leukocytosis) and decreased number of platelets (i.e., thrombocytope nia) are common in alcoholic hepatitis. Thrombocytopenia may be transitory, but in patients with concomitant cir rhosis, it is persistent. Markers of severe alcoholic hepatitis or cirrhosis include elevated levels of bilirubin (a yellow-orange substance generated in the liver), pro longed time required for a blood sample to clot (i.e., prothrombin time [PT]), and a low level of the main circulating protein in the bloodstream (i.e., albumin), which is synthesized by the liver (i.e., hypoalbuminemia). The most commonly used prognostic index in alcoholic hep atitis is Maddrey's Discriminant Function (DF), which is calculated by this equation: 4.6 [PT(patient) -PT(control)] + total bilirubin (mg/dl).
If this value exceeds 32, the mortality rate during a current hospitalization may exceed 50 percent (Maddrey et al. 1978;Carithers et al. 1989). There also is evidence that blood concentrations of proteins (i.e., cytokines) that promote inflammation-such as tumor necrosis factor alpha (TNF-α), interleukin-6, and interleukin-8-correlate with mortality in patients with alcoholic hepatitis (McClain et al. 1993), but levels of these cytokines are not determined in routine clinical practice. Liver biopsy mainly is used to clarify atypical cases, to better define the con tribution of alcohol in patients with possible non-alcohol-related coexisting conditions (e.g., hepatitis C, use of lipidlowering medications), and to deter mine the severity of liver disease. Many laboratories are conducting research to evaluate biomarkers or identifier proteins for detecting ongoing alcohol abuse and ALD. The importance of genetic varia tions in alcoholism and ALD among individuals also is under active investiga tion. New tests may provide novel ways of identifying alcohol abuse, suscepti bility to liver injury, and mechanisms of liver injury, and of detecting and monitor ing liver injury.

Treatment of ALD
Treatment strategies for ALD include lifestyle changes to reduce alcohol con sumption, cigarette smoking, and obe sity; nutrition therapy; pharmacological therapy; and possibly liver transplanta tion (see textbox). (Liver transplantation is discussed in detail in the article by Anantharaju and Van Thiel in this issue.)

Lifestyle Changes
Abstinence from alcohol is vital in order to prevent further liver injury, scarring, and possibly liver carcinoma; it appears to benefit patients at every stage of the disease. Fatty liver is reversible with abstinence. Although evaluations of the effects of abstinence on the progres sion of ALD are few and have involved retrospective, nonrandomized trials, virtually all these studies have shown beneficial effects of abstinence (Powell and Klatskin 1968;Merkel et al. 1996). Patients with either compensated or decompensated cirrhosis benefit from abstinence. Thus, all patients with ALD should be encouraged to abstain from alcohol consumption. Newer medica tions to facilitate abstinence, such as naltrexone and acamprosate, have been shown to be effective in some chronic alcoholics, but no large multicenter stud ies have evaluated these medications in patients with ALD.
Many people who drink alcohol also smoke cigarettes. In European studies, fibrosis worsens more rapidly in ALD patients who smoke cigarettes (Klatsky and Armstrong 1992;Corrao et al. 1994). Patients with hepatitis C who drink also deteriorate faster if they smoke cigarettes (Pessione et al. 2001). Cigarette smoking causes oxidative stress, a con dition that arises when an overabun dance of free radicals is present in the body, which may be a factor leading to accelerated liver disease in smokers.
Obesity is associated with the devel opment of fatty liver and nonalcoholic steatohepatitis, a disorder that is histo logically identical to alcoholic hepatitis. Body mass index has been shown to be an independent risk factor for the development of ALD (Raynard et al. 2002). An increasingly large subset of ALD patients are obese, with alcohol intake as a source of excess and empty calories (that is, having no nutritional value). Thus, as with many other gas trointestinal disorders (e.g., gastro esophageal reflux disease), the initial approach to treating ALD is lifestyle modification to reduce alcohol consump tion, cigarette smoking, and obesity.

Nutrition Therapy
Malnutrition is prevalent in alcoholic hepatitis and cirrhosis, especially in end-stage ALD, and can range from deficiency in individual nutrients (e.g., zinc, folate) to global proteincalorie malnutrition. Researchers at the VA Cooperative Studies Program have conducted some of the most extensive studies of nutri tional status in patients with alcoholic hepatitis (Mendenhall et al. 1995). The first of these studies (VA Cooperative Study 119) demonstrated that virtually every patient with alcoholic hepatitis had some degree of malnutrition. Patients had an average alcohol consumption of 228 grams per day, with almost 50 percent of energy intake coming from alcohol. The severity of liver disease generally correlated with the severity of malnutrition.
A followup VA study on alcoholic hepatitis (VA Cooperative Study 275) found similar results. In both of these studies, patients were given a balanced 2,500-kilocalorie hospital diet, moni tored carefully by a dietitian, and were encouraged to follow it. In the second study, patients in the treatment group also received a liquid nutritional sup plement high in three amino acids that help to stimulate protein synthesis (which was administered as an oral food sup plement), as well as the anabolic steroid oxandrolone. In neither study were patients fed by tube if voluntary oral intake was inadequate (probably a design flaw, in retrospect). Voluntary oral food intake correlated in a stepwise fashion with 6-month mortality data-that is, almost all patients who voluntarily con sumed more than 3,000 kcal per day still were living at the end of the 6-month period, whereas more than 80 percent of those consuming less than 1,000 kcal per day died within that time (see figure 2) (Mendenhall et al. 1995). Moreover, the degree of malnutrition correlated with the development of seri ous complications such as encephalopa thy, ascites, and hepatorenal syndrome in nutritional status and immune func tion (Hirsch et al. 1999).
VA Cooperative Study 275 found that the combination of an anabolic steroid and an oral nutritional supplement reduced the mortality rate of patients who had moderate protein-energy malnu trition (Mendenhall et al. 1995). Those with severe malnutrition did not signif icantly benefit from the therapy, possi bly because their malnutrition was so advanced that no intervention, includ ing nutrition, could help. Kearns and colleagues (1992) showed that patients with ALD who were hos pitalized for treatment and given an enteral nutritional supplement via tube feeding had significantly improved serum bilirubin levels and liver function. More over, a major randomized study of enteral nutrition versus steroids in patients with alcoholic hepatitis showed similar over all initial outcomes, as well as fewer long-term infections in the nutrition group (Cabre et al. 2000). This impor tant study suggests that aggressive nutri tional support is as effective as treatment with prednisone (an immunosuppressive medication), with its potential compli cations (e.g., infections, diabetes, osteo porosis), in hospitalized patients with alcoholic hepatitis.
Thus, traditional nutritional supple mentation clearly improves nutritional status and, in some instances, hepatic function and other outcome indicators in alcoholic hepatitis and cirrhosis.

Pharmacological Therapy
Although ALD remains a major cause of morbidity and mortality in the United States, there is no FDA-approved therapy for either alcoholic cirrhosis or alcoholic hepatitis. However, several drugs have been used "off label." Propylthiouracil (PTU). Orrego and colleagues (1987) examined long-term PTU therapy in more than 300 patients with various types of liver disease, includ ing ALD. In this study, mortality was reduced by nearly 50 percent in patients receiving PTU. A recent review (Rambaldi (Mendenhall et al. 1995).
Interest in nutrition therapy for cir rhosis was stimulated when Patek and colleagues (1948) demonstrated that a nutritious diet improved the 5-year out come of patients with alcoholic cirrho sis compared with patients consuming an inadequate diet. Several recent stud ies have found improved outcomes in cirrhosis patients who were given nutri tional support. Hirsch and colleagues (1993) demonstrated that outpatients receiving a nutritional support product (1,000 kcal, 34 grams protein) through a feeding tube (i.e., enteral nutritional support) had significantly improved protein intake and significantly fewer hospitalizations. These investigators subsequently gave enteral nutritional support to outpatients with alcoholic cirrhosis and observed an improvement  (Carithers et al. 1989), but a large multi center VA study yielded negative results (Mendenhall et al. 1984). Steroids have been found to be effective against severe acute alcoholic hepatitis by most metaanalyses, including the most recent study by Mathurin and colleagues (2002). These investigators reported significantly improved survival at 28 days (85 per cent vs. 65 percent) in severely ill alco holic hepatitis patients having a DF greater than 32. This survival advantage may extend to 1 year but not 2. Inde pendent prognostic factors associated with survival at 28 days in this metaanalysis were steroid treatment, age, and serum creatinine levels. Patients with infections, gastrointestinal bleeding, and many other common complications were excluded from these studies. Most investigators agree that if cor ticosteroids are to be used, they should be reserved for patients with severe liver disease (i.e., DF greater than 32), and possibly those with hepatic encephalop athy. Steroids have well-documented side effects, including enhancing risk of infection, which already is substan tial in patients with alcoholic hepatitis. Thus, a major disadvantage to cortico steroids is that they cannot be used by many patients with alcoholic hepatitis.

Complementary and Alternative
Medicine (CAM) Agents. CAM agents have had some success in patients with liver disease and are widely used. Research demonstrates a strong rationale for using many of these CAM agents, such as S adenosylmethionine, but shows that others may have no efficacy or may even cause harm, including liver injury.

Diagnosis and Treatment of the Complications of ALD
Proper diagnosis and management of the complications of ALD are vital to decreasing the deterioration of illness, improving quality of life, and possibly decreasing mortality. The complications Diagnosing and Treating Alcoholic Liver Disease of ALD reviewed here are: ascites (accu mulations of fluid in the abdominal cavity), infections in this fluid that develop without any apparent cause (i.e., spontaneous bacterial peritonitis [SPB]), hepatorenal syndrome, and esophageal varices.

Ascites
Ascites is one of the most common complications of advanced liver disease and generally indicates a poor progno sis and a high likelihood of death. Approximately 8 of every 10 patients who have ascites in the United States have it as a consequence of cirrhosis of the liver. It is estimated that 3 of every 10 patients who have cirrhosis without complications will develop ascites within the next 5 years. In patients with ascites, the likelihood of death in the following year is approximately 50 percent, com pared with 10 percent for cirrhosis patients without complications. Ascites cases can be classified as easily treatable or refractory and difficult to control. Patients with the latter type are likely to develop hepatorenal syndrome (Garcia-Tsao 2001).
Ascites leads not only to aesthetic changes in body shape but, more impor tantly, to: • Increased risk of spontaneous infec tion of the ascitic fluid.
• Development of abdominal hernias where the abdominal wall muscle becomes weakened and part of the abdomen protrudes (sometimes to the extreme of spontaneous rupture) (see figure 3).
• Difficulty breathing because of pressure of the abdomen on the respiratory muscles.
• Decreased food intake, with pro gressive malnutrition.
• Decreased physical activity with consequent loss of muscle mass.
Treating ascites does not seem to prolong life in cirrhotic patients but improves the quality of life and protects patients from spontaneous infections of the fluid, which are associated with high death rates.
Patients who develop ascites for the first time, those with ascites who are admitted to the hospital because of illness, those who have difficult-to-control ascites, and those who develop symptoms because of tense ascites (i.e., the abdomen is tight with ascites)-all should have the fluid removed for diagnostic evaluation and to lessen discomfort in the abdomen. Because these patients are at high risk of infection in the fluid and because the fluid accumulation may be a conse quence not only of liver disease but also of other associated disorders, this fluid should be thoroughly evaluated. Evaluation should include a cell count (Runyon 1997(Runyon , 1998 as well as deter minations of total protein and albu min. At around the same time, a blood sample should be checked to measure the amount of albumin in order to facilitate interpretation of the findings on the ascitic fluid. For patients who have ascites because of portal vein hypertension, determining serum albu min concentration-ascitic albumin concentration (SAAG) is recommended. SAAG is calculated by subtracting the albumin concentration of the ascitic fluid from the albumin concentration of a serum specimen obtained on the same day. Patients with SAAGs of 1.1 grams per deciliter (g/dl) or higher may have cirrhosis or alcoholic hepatitis, among other conditions.
To control the formation of ascites, patients must eliminate more sodium than they acquire through diet. Patients with cirrhosis and ascites tend to retain sodium very efficiently, and most patients need to have dietary sodium restricted to less than 2 grams per day (88 mEq [milliequivalent, or the number of grams of solute dissolved in one milliliter of solution]). To prevent additional ascites, a patient who is following a 2-gram sodium diet needs to lose at least 78 mEq sodium per day through the urine in addition to the 10 mEq that are lost regularly through the skin. Research has shown that if a person is eliminat ing a ratio of sodium to potassium through urine that is greater than 1, that person will be eliminating at least 78 mEq sodium per day in urine. To be able to eliminate this amount of sodium, most patients need to take diuretics.
Patients who have no swelling of the extremities should not lose more than half a kilogram of weight per day in order to control ascites. Those who have swelling in the extremities may be able to lose up to 1 kilogram per day. Fluid restriction is not required except in patients with very low sodium concen tration in the blood. So that patients will not become dehydrated, the dose of diuretics is adjusted based on the patients' response to the medication (i.e., it is titrated) to obtain a zero balance of sodium once the ascites has been controlled (Runyon 1997(Runyon , 1998Andy and Ke-Qin 2001). Once a patient has developed ascites, he or she is at high risk of death. For that reason, liver trans plantation should be contemplated if the patient is a suitable candidate.

Spontaneous Bacterial Peritonitis (SBP)
Of patients hospitalized with ascites, between 10 percent and 30 percent will develop SBP. This infection is thought to occur either by spontaneous passage of normal bacteria that reside in the gut into the ascitic fluid, or by seeding of bacteria into the blood from a distant source (e.g., a urinary infection or lung infection), leading to growth of this bacteria in the ascitic fluid (O'Grady et al. 2000).
Patients who have low protein con centrations in the ascites (less than 1.5 g/dl) are at higher risk of developing SBP. Once a patient has had an episode of SBP, there is a 7 in 10 chance that a new episode will occur within the next year. With every episode, 2 to 3 of every 10 patients will die from complications of the infection, and only 3 of every 10 are expected to survive for 2 years (Garcia-Tsao 2001).
The diagnosis of SBP is made when high numbers of a type of white blood cell that is especially protective against bacterial infections (i.e., polymorphonu clear cells [PMN]) are found in the ascitic fluid (i.e., in excess of 250 per ml). Patients are diagnosed as having SBP if bacteria are found in the ascitic fluid, but the concentration of bacteria in the fluid is extremely low-an esti mated 1 bacterium per milliliter of fluid-so that the bacteria cannot be seen by examining the fluid under the microscope. In order to have a reasonable chance of getting a positive culture, the fluid should be injected at the bedside into blood culture bottles specially designed to recover small amounts of bacteria. This technique will detect the vast majority of infections. If improper techniques are used (e.g., sending the fluid to the laboratory to be placed on a culture plate), chances of proper diag nosis decrease to 4 out of 10.
Patients with SBP may not have symptoms, or manifestations of the infection may appear to be unrelated to

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After 2 years of absti the abdominal cavity. For example, SBP patients may have confusion, changes in kidney function, poorly controlled ascites, or overall progressively deteriorat ing health. Despite the fact that more than half of the patients with SBP com plain of some degree of abdominal pain or discomfort, the physical exam of the abdomen usually is completely benign.
Usually only one type of bacteria appears in the culture of patients who have SBP. Clinicians should suspect the possibility of a secondary peritonitis (e.g., some intra-abdominal perforation or abscess formation in the abdomen) if (1) multiple kinds of bacteria are recovered from the culture, or (2) the patient develops an infection consistent with SBP but in the presence of total protein concentration in the ascitic fluid of more than 1.5 g/dl, or (3) the patient fails to respond promptly to proper antibiotic therapy. A secondary infection also should be suspected if direct examination of fluid under the microscope shows bacteria because, as mentioned, the concentration of bacteria in SBP is so low that bacteria should not be detectable by microscopic exam ination (Andy and Ke-Qin 2001;Garcia-Tsao 1992).
Patients who develop SBP are at extremely high risk of developing kidney dysfunction and hepatorenal syndrome. Expansion of the volume within the blood vessels (i.e., the intravascular vol ume) using intravenous albumin infu sions has been shown to decrease the frequency of hepatorenal syndrome and, for that reason, improves survival rates in patients who develop SBP (Sort et al. 1999). Because of concerns about kidney toxicity, it is important to avoid antibiotics or other medications that may exacerbate kidney damage. Current therapy for SBP includes use of the antibacterial drug cefotaxime.
Patients at special risk for SBP are those who are hospitalized and have a total protein concentration in the ascitic fluid that is less than 1.5 g/dl, those who have gastrointestinal bleeding from any source, and those who have had previous episodes of SBP (Andy and Ke-Qin 2001). Prophylactic therapy (i.e., anti biotic treatment) is indicated for all these groups of patients.

Hepatorenal Syndrome
Hepatorenal syndrome is the deteriora tion of kidney function in patients who have acute or chronic liver failure but otherwise healthy kidneys. This disorder may occur spontaneously but more often is the result of an infection, an episode of gastrointestinal bleeding, or overly aggressive use of diuretics. There are two types of hepatorenal syndrome: Type I conveys the highest risk of death and develops rapidly over a couple of weeks; Type II progresses more slowly, usually over several months. The diag nosis of hepatorenal syndrome requires fulfillment of all of the following criteria: • Deterioration of kidney function demonstrated by a concentration of creatinine in the blood of more than 1.5 mg/dl or a decrease in creatinine clearance to less than 40 milliliters per minute.
• No evidence of dehydration, no exposure to a drug or infection that causes kidney toxicity, and absence of severe low blood pressure (shock).
• Failure to respond to discontinua tion of diuretics or to treatment with 1.5 liters of saline solution to expand blood volume.
• No evidence of obstruction of urine flow or primary kidney disease, as demonstrated by ultrasound exam.
• Little or no protein in the urine.
The majority of patients who will develop hepatorenal syndrome will first develop diuretic-resistant ascites, usually with very low sodium in the urine (i.e., less than 10 mEq/L). In general, among patients who have ascites, the risk of developing hepatorenal syndrome is 2 in 10 during the first year and 4 in 10 during the first 5 years. Among patients with Type I hepatorenal syn drome, the estimated mortality without appropriate therapy is 80 percent after 2 weeks and 90 percent after 10 weeks (Gines et al. 1993).
Hepatorenal syndrome is thought to result from a severe contraction of the artery that feeds the kidney, which may occur as a response to excessive relax ation of the vessels in the rest of the body and a relatively low volume of blood inside the vascular system. Thus, the first approach to treatment of this disorder is to try to expand vascular volume and then to increase the degree of contraction of vessels other than the kidney artery.
Several strategies have been used to reverse hepatorenal syndrome. The first involves intravenous infusions of albu min (to expand vascular volume), fol lowed by administration of ornipressin, a medication that increases the contrac tion of most of the vessels in the body (Guevara et al. 1998a). Similar effects with fewer complications have been obtained using intravenous albumin with terlipressin, which causes vessel contraction more safely Moreau et al. 2002).
In the United States, neither orni pressin nor terlipressin is available, and the most popular intervention for hep atorenal syndrome is to expand blood volume using intravenous albumin, then to administer midodrine and octreotide to regulate vascular contrac tion (Angeli et al. 1999). For patients who cannot tolerate medication by mouth, intravenous albumin can be used, followed by continuous infusion of norepinephrine (Duvoux et al. 2002). With the latter two regimens, benefi cial effects usually can be seen by day 10 of therapy and, if not successful, the treatment usually is discontinued after 15 days. Patients who do respond can complete at least 2 weeks of therapy, and after that, therapy can be discon tinued, usually without deterioration of kidney function.
Other therapies are being used, including the transjugular intrahepatic portal systemic shunt (TIPS), in which a long catheter is inserted via the jugu lar vein in the neck, advanced into a hepatic vein and then into a large branch of the portal vein in the liver. Using an inflatable balloon-tipped catheter tube, the section between the portal vein branch and the hepatic vein is widened and then kept open (stented) with a cylindrical wire-mesh stent (Guevara et al. 1998b). This helps to lower the increased pressure in the portal vein. In addition, hepatorenal syndrome has been treated using high doses of antioxidants (Holt et al. 1999). More recently, a system known as MARS (molecular absorbent recirculating system) has been used (Mitzner et al. 2000); with this treatment, a patient's blood is transported to a fil ter, where it is mixed with albumin, which carries the toxins out of the blood.
Although these treatments are avail able, hepatorenal syndrome will very likely recur, and patients should be moved quickly in the direction of pos sible liver transplantation.

Esophageal Varices
Cirrhosis causes an increase in pressure in the fine net of blood vessels inside the liver. This pressure is transmitted back to the portal vein and onto the veins that form it. Because of the high pressure on the veins forming the por tal vein and the portal vein itself, blood tries to escape, forming new collateral veins (i.e., the increased pressure causes very small varices to grow larger). Many of these veins are localized superficially inside the esophagus and the upper part of the stomach. When these veins engorge because of increased pressure, they are called varices.
Varices in the esophagus and stomach are present in about half of all cirrhosis patients. Each year, 5 percent to 20 percent of patients with cirrhosis expe rience the formation of varices. Once varices have been formed, 5 percent to 15 percent become large varices (Garcia and Sanyal 2001). Large varices are highly likely to rupture. Patients with more severe liver disease tend to have more varices, and their varices tend to be larger. Spontaneous rupture of these varices and severe bleeding occur when the pressure on the portal vein, expressed as the difference between the pressure in the portal vein and the pressure in the vein that drains out of the liver (i.e., the portal pressure gradient), is greater than 12 mm of mercury. Large varices have a 2-year risk of bleeding sponta neously in approximately 3 of every 10 cases. Small varices have a risk of only 1 in 10 ( Garcia and Sanyal 2001). Because it is difficult to determine that varices are developing, endoscopic evaluation of the esophagus and stomach is rec ommended at 1-to 2-year intervals in patients with cirrhosis to determine whether varices have formed and if they are large enough to require treat ment to prevent bleeding. Varices in the esophagus that are large or show evidence of high risk for bleed ing should be considered for treatment to prevent bleeding (i.e., primary pro phylaxis), such as the use of a class of drugs that block the action of the invol untary nervous system on the heart, and therefore relieve stress on the heart (i.e., nonselective beta blockers). An analysis of 11 prospective studies evalu ating the effectiveness of nonselective beta blockers at preventing initial variceal bleeding showed that beta blockers decreased the risk of first bleed by at least 40 percent (25 percent in control subjects vs. 15 percent in the treatment group) after a median of 2 years (Garcia-Tsao 2001). Isosorbide mononitrate and isosorbide dinitrate, which dilate both the veins and the arteries, have been evaluated for this purpose but have proven to be ineffective as single agents. Adding low doses of these medications, however, to a regimen of nonselective beta blockers may be of some help.
Treatment in the form of ligation of varices, in which elastic bands are placed around varices using a device attached to the end of the endoscope, also has proven to be effective but usually is reserved for patients who have large varices and cannot tolerate beta block ers (see figure 4). As mentioned, patients with esophageal varices may bleed spontaneously. Approximately half of these patients will stop bleeding spon taneously. The frequency of death for each of these episodes is 3 in 10. It is estimated that bleeding will recur within 6 weeks in 4 of 10 patients who have esophageal variceal bleeding. Thus, treatment of bleeding from esophageal varices has two components: immediate treatment to control the present bleed and additional treatment to prevent consequent bleeding (i.e., secondary prophylaxis).
In the United States the initial med ical intervention for suspected variceal bleeding is to administer intravenous octreotide, which has been shown to safely and effectively control variceal bleeding by regulating vascular contrac tion and decreasing the pressure in the portal venous system (Garcia and Sanyal 2001;D'Amico et al. 1999). The method that has proven to be the best in con trolling acute variceal hemorrhage is endoscopic banding of the esophageal varices. When banding is not possible, injecting the varices with scarring sub stances also can be used. Because cir rhotic patients with gastrointestinal bleeding are at high risk of developing serious infections, a prophylactic 7-day course of the antibiotic norfloxacin is recommended. A patient who has had the first episode of variceal bleeding faces an 8-in-10 chance of bleeding again in the next 3 years. In addition, treatment with nonselective beta blockers, in a manner similar to primary prophylaxis, should be given to patients who are not already receiving these drugs. Patients who cannot tolerate the medication, or for whom beta blockers are contra indicated, can be treated with repeated banding of the varices at 10-to 14-day intervals.
Patients who rebleed despite therapy with beta blockers and endoscopy should be considered for the TIPS pro cedure or surgery performing a distal spleno-renal shunt, thereby decreasing the high pressure of the veins by con necting the high-pressure vessels to the inferior vena cava system, which is a lowpressure system (i.e., it carries oxygenpoor blood to the heart from the lower half of the body). Despite the fact that TIPS is more effective than endoscopic therapy in decreasing rebleeding from esophageal varices (19 percent rebleed ing with TIPS vs. 47 percent with endo scopic therapy), 1 in 3 of these patients will develop hepatic encephalopathy after TIPS, and this intervention does not affect survival rates. Because of the problems with encephalopathy and the cost of TIPS, this approach usually is reserved as rescue therapy. Liver trans plantation is, of course, definitive ther apy and should be considered for all of these patients.

Conclusions
In summary, it now is generally possible to accurately diagnose ALD, and new biomarkers or identifier proteins for detecting ongoing alcohol abuse and ALD are being investigated, as is the role of genetics in ALD. Although there are no FDA-approved therapies for alcoholic liver disease, lifestyle changes, nutritional support, and "off-label" therapies such as PTX can improve out come. Similarly, new therapies for com plications are improving quality of life and, in some cases, even reducing mor tality rates. ■